The ways in which triarylethylene antiestrogens such as clomiphene, chlorotrianisene, nitromiphene, and tamoxifen suppress hormone dependent cell growth, including that of breast cancer cells are not fully understood. A complicating factor in developing such an understanding is an incomplete awareness of the ways in which drug metabolizing enzymes modulate antiestrogenic activity. A variety of liver microsomal metabolites resulting from oxidative biotransformation of each of the above compounds have been characterized. Most of these metabolites had estrogen receptor affinities and antiestrogenic (antiuterotropic) activities equal to or greater than those of the respective parent drugs, in the immature rat. The overall objective of this application is to determine the time course of target tissue (uterine) distribution of each of the above compounds in the immature rat, with the aims of (a) determining the amounts of previously characterized liver microsomal metabolites present; (b) isolating and characterizing any new metabolites, not found in our liver microsomal studies nor reported in other in vivo studies; (c) assessing the effects of co-substrates for drug metabolizing enzymes, which are used in combination therapy with antiestrogens, on quantitative distribution of antiestrogens and respective metabolites. Also, identification and quantitation of each drug and its metabolites in plasma and liver tissue will be carried out, since blood and liver have been shown to be important sites of distribution of triarylethylene antiestrogens. These studies will be conducted using tritium and/or carbon-14 labeled forms of the antiestrogens. Thin layer chromatography will be used extensively in metabolite isolation, determination of purity of labeled and unlabeled drugs, and in quantitative analysis of biological extracts. These studies will be carried out using Sprague-Dawley rats. Results of this work should help to define the extent to which drug metabolizing enzymes modulate the pharmacological properties of triarylethylene antiestrogens.